Diabetes affects harmful influences on human health, causing various complications. Diabetes may be classified into type 1 diabetes where insulin is not excreted due to the destruction of pancreatic cells, and type 2 diabetes where insulin is not produced due to the other conditions or the body does not response to insulin. The type 2 diabetes occupies 90% or more of the total patients suffered from diabetes. Typical complications accompanied with diabetes include hyperlipidemia, hypertension, retinosis, renal failure, etc. (Zimmer P., et al., Nature, 2001, 414, 782). As the therapeutic agents for diabetes, sulfonyl ureas (facilitating insulin secretion in the pancreatic cells), biguanides (suppressing glucose production in the liver), α-glucosidase inhibitors (suppressing glucose uptake in the bowels), etc. are used, among which peroxisome proliferator-activated receptor gamma (PPAR γ) agonists (thiazolidinediones, increased insulin sensitivity) are recently focused. However, these agents show some side effects, such as weight gain, according to the respective mechanisms of action (Moller D. E., Nature, 2001, 414, 821). Thus, there has been a need for the development of an agent for the treatment of diabetes, which does not cause such side effects.
For a normal healthy person, blood glucose is accurately controlled within a safe and narrow physiological range by means of various endocrine glucostatic systems. If such glucostatic systems do not work, glucose intolerance occurs first, which is gradually grown to the type 2 diabetes. Dysfunction of such control mechanism is resulted from (i) decrease of secretion of insulin from the pancreatic cells, (ii) increases of insulin resistance in the liver, cells of adipose tissue, and cells of skeletal muscle, and (iii) excess production of blood glucose by the liver.
According to many research outputs obtained during the past forty years, glucokinase that belongs to hexokinase IV series are involved in the first step of glucose metabolism to directly control the glucose content in the blood, whereby it plays an important role in the maintenance of glucose homeostasis in the body.
The glucokinase in the pancreatic cells can determine the thresholds of glucose-stimulated insulin release (GSIR) by acting as a glucose sensor. The glucokinase decreases blood glucose by phosphorylating glucose into glucose-6-phosphate consuming ATP, and keeping glucose-6-phosphate in the cells (Meglasson M. D. and Matschinsky F. M., Diabetes Metab Rev, 1986, 2, 163).
On the other hand, the glucokinase in hepatocytes has the feature of being short-term controlled by glucokinase regulatory protein. Glucokinase regulatory protein forms a 1:1 complex with glucokinase, and acts as a “competitive inhibitor” against glucose to confine the inactivated glucokinase within the nucleus and to protect and stabilize it from other proteins such as decomposition enzymes, etc. It has been reported that fructose-6-phosphate further stabilizes glukinase regulatory protein, whereas fructose-1-phosphate separates glucokinase from glucokinase regulatory protein and transfers it from nucleus to cytoplasm to keep its activated state (Van Schaftingen E., Eur J Biochem, 1989, 179). The glucokinase in hepatocytes appropriately controls the glucose metabolism in the liver. That is, glucose uptake and production are effectively controlled under the satiation or fast state (Agius L., et al., J Biol Chem, 1996, 271, 30479).
As explained above, glucokinase activates the two functions of (i) direct control of blood glucose in the liver, and (ii) facilitation of insulin secretion within the physiological range after detection of glucose concentration in the pancreas, and thus, plays a very important role in the maintenance of glucose homeostasis.
The experimental results in many rodent models suggested that glucokinase is a key regulator in the maintenance of glucose homeostasis. Rats lacking the glucokinase gene function in pancreatic beta cells show a significant hyperglycemic symptom, and rats lacking the glucokinase gene function in hepatocytes show depressed glucose uptake and hyperglycemic symptom. On the other hand, when the glucokinase gene is over expressed in hepatocytes of normal rats, amelioration effect of glucose tolerance is shown (Rossetti L., et al., Am J Physiol, 1997, 273, E743). And, the over expression of glucokinase in diabetic rats induces amelioration of glucose tolerance and blood glucose lowering effect under the fast state (Desai U. J., et al., Am J Diabetes, 2001, 50, 2285).
Hitherto, about 200 glucokinase gene mutants have been clinically reported for humans. Patients of MODY (maturity onset diabetes of the young)-2, a subtype of type 2 diabetes, showed some decrease of glucokinase activity due to the loss-of-function mutation and hyperglycemia due to the decrease of insulin secretion. On the contrary, patients of PNDM (permanent neonatal diabetes) and PHHI (persistent hyperinsulinemia hypoglycemia of infancy) showed serious hypoglycemia due to the glucokinase activation based on the gain-of-function mutation (Matsinsky F. M., et al., Frontiers in Daibetes, 2004, 16, chapter 4-7). Such phenotypes of glucokinase-associated diseases suggest that glucokinase plays an important role in the maintenance of glucose homeostasis in the body, which leaves a clue to develop a drug for enhancing the glucokinase activity.
According to the recent studies (Nakamura A., et al., Impact of small molecule glucokinase activator on glucose metabolism and beta cell mass, Endocrinology, 2008, Nov.), glucokinase activators facilitate pancreatic beta cell division to improve the glucose metabolism by maintaining the pancreatic cell mass. Also, it has been reported that glucose metabolism and hyperglycemia can be normalized by the restoration of hepatocellular glucokinase activity only in 20 week old ZDF (Zucker diabetic fatty) rat model (Torres T. P., et al., Restoration of hepatic glucokinase expression corrects hepatic glucose flux and normalize plasma glucose in zucker diabetic fatty rats, 2008, Endocrinology, Oct.), which suggests that hepatocyte-specific glucokinase activators may be developed as a therapeutic agent that can be used for the type 1 diabetics as well as the chronic type 2 diabetics in the future.
A lot of researches for glucokinase activators have been reported. As the recently published patents, WO2007/007910A1, WO2006/112549A1, WO2007/031739, WO2007/037534, WO2007/043638, WO2007/028135, US20070099930, WO2007/041365, WO2007/051847, WO2007/053345, WO2007/007910, WO2006/049304, etc. may be mentioned.
The present inventors extensively studied glucokinase activators, and as a result have confirmed that the indole compounds of formula (1) are effective as glucokinase activators. Thus, they completed the present invention that relates to glucokinase activators based on indole structure.